Human papillomavirus (HPV), primarily HPV 16 & 18, are strongly implicated in the development of squamous cell carcinoma of the penis. Three carcinoma in situ are associated with squamous cell carcinoma of the penis:
1) Bowen's disease which presents as leukoplakia on the shaft. Around 1/3 progress to squamous cell carcinoma
2) Erythroplasia of Queyrat, a variation of Bowen's disease, presenting as erythroplakia on the glans
3) Bowenoid papulosis, which histologically resembles Bowen disease, but presents as reddish papules.[7]

When associated with the prostate, squamous cell carcinoma is very aggressive in nature. It is difficult to detect as there is no increase in prostate specific antigen levels seen; meaning that the cancer is often diagnosed at an advanced stage.

Cancer can be considered a very large and exceptionally heterogeneous family of malignant diseases, with squamous cell carcinomas comprising one of the largest subsets.[8][9][10] All squamous cell carcinoma lesions are thought to begin via the repeated, uncontrolled division of cancer stem cells of epithelial lineage or characteristics.[citation needed] Squamous cell carcinomas arise from squamous cells, which are flat cells that line many areas of the body. Accumulation of these cancer cells causes a microscopic focus of abnormal cells that are, at least initially, locally confined within the specific tissue in which the progenitor cell resided. This condition is called squamous cell carcinoma in situ, and it is diagnosed when the tumor has not yet penetrated the basement membrane or other delimiting structure to invade adjacent tissues. Once the lesion has grown and progressed to the point where it has breached, penetrated, and infiltrated adjacent structures, it is referred to as "invasive" squamous cell carcinoma. Once a carcinoma becomes invasive, it is able to spread to other organs and cause the formation of a metastasis, or "secondary tumor".

Keratoacanthoma is a low-grade malignancy of the skin. It originates in the pilo-sebaceous glands, and is similar in clinical presentation and microscopic analysis to squamous cell carcinoma, except that it contains a central keratin plug. Statistically, it is less likely to become invasive than squamous cell carcinoma.

Marjolin's ulcer is a type of squamous cell carcinoma that arises from a non-healing ulcer or burn wound. More recent evidence, however, suggests that there may be genetic differences between squamous cell carcinoma and marjolin's ulcer which were previously underappreciated.[12]

Basaloid squamous cell carcinoma is characterized by a predilection for the tongue base.[13]

Clear-cell squamous cell carcinoma (also known as "clear-cell carcinoma of the skin") is characterized by keratinocytes that appear clear as a result of hydropic swelling.[13]

Signet-ring-cell squamous cell carcinoma (occasionally rendered as "signet-ring-cell squamous cell carcinoma") is a histological variant characterized by concentric rings composed of keratin and large vacuoles corresponding to markedly dilated endoplasmic reticulum.[13] These vacuoles grow to such an extent that they radically displace the cellnucleus toward the cell membrane, giving the cell a distinctive superficial resemblance to a "signet ring" when viewed under a microscope.

SCC is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of cells of epithelium, or cells showing particular cytological or tissue architectural characteristics of squamous cell differentiation, such as the presence of keratin, tonofilament bundles, or desmosomes, structures involved in cell-to-cell adhesion.